EGFR EXON 19 DELETION OR L858R MUTATIONS….Progression on erlotinib (± ramucirumab or bevacizumab), afatinib, gefitinib, or dacomitinib….SUBSEQUENT THERAPY...T790M...Osimertinib (category 1) (if not previously given).

UpSwinG was a non-interventional, global, multi-center study (NCT04179890)...in a real-world practice setting who met the following criteria were retrospectively reviewed between November 2019 and July 2020: aged ≥ 18 years with EGFR mutation-positive (Del19 or L858R), TKI-naïve, advanced NSCLC treated with first-line afatinib and, following detection of T790M, second-line osimertinib....The ORR with osimertinib was 45.2% (Table 3); median DoR was 6 months (IQR: 2–10). The DCR was 86.7%. Of 166 evaluable patients, two (1.2%) had a CR, 73 (44.0%) had a PR, 69 (41.6%) had SD and 22 (13.3%) had progressive disease. ORR with osimertinib was consistent across subgroups (Table 3)....This study demonstrated promising activity of...osimertinib in patients with...acquired T790M.

...pts with EGFRm+ NSCLC (Del19 or L858R) treated with 1st-line afa/2nd-line osi in regular clinical practice (n = 191; all T790M+)...ORR with afa and osi was 74% and 45%....These data support the previous GioTag study and show encouraging activity of sequential afa/osi in pts with EGFRm+ NSCLC and acquired T790M.

Of the 106 patients, 60 (56.6%) had PR, 38 (35.9%) had SD, and 7 (6.6%) had PD. DCR and ORR were 93.4% and 57.5%, including 1 patient with complete remission (CR)....In patients with EGFR exon 19 deletion and exon 21 L858 mutation, the median PFS was 11 (9.2, 12.8) and 12 (9.2, 14.8) months, respectively (p = 0.833)....Osimertinib can effectively treat advanced NSCLC with T790M mutations independently of previous treatment lines.

We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKIs between....A total of 45 patients were available for evaluation of the disease response in these two genotypes. The DCR was 100% (29/29) in patients with T790M + /19del + and 93.8% (15/16) in patients with T790M + /L858R + (P = 0.356).

Here, we report the case of a patient who was diagnosed as stage IV NSCLC with EGFR 21 exon L858R mutation combined with EGFR 20 exon T790M mutation...the patient received a regular double dose of Tagrisso. The patient’s progression-free survival (PFS) was extended by 7 months, and the OS reached more than 5 years, which is rare in clinical practice.

Osimertinib was administered at different doses to EGFRL858R–T790M double-mutant H1975 cells and to EGFRWT A549 NSCLC cells in 2D experiments. Apoptosis was measured by flow cytometry using markers for viability and mitochondrial-transmembrane potential (ΔΨm) decay (Figs. 1A and S1). Unlike cisplatin (Fig. S1A, B), osimertinib caused higher apoptosis in H1975 vs. A549 cells as expected (Fig. S1C, D), due to the intrinsic cisplatin-resistance of H1975 cells and to the higher binding affinity of osimertinib towards EGFRL858R–T790M vs. EGFRWT.